1. Technical Field
The invention relates generally to neural progenitor cells and more specifically to the regulation of tyrosine hydroxylase expression and treatment of catecholamine-related diseases.
2. Background Information
During development, neural stem cells differentiate into the different types of neurons and glia found in the adult central nervous system (CNS) and peripheral nervous system (PNS). In general, these different types of neurons are classified based on the particular types of neurotransmitters they produce. For example, dopaminergic neurons produce dopamine, while noradrenergic neurons produce norepinephrine. The neurotransmitters dopamine and norepinephrine belong to a class of compounds called catecholamines. A catecholamine is an ortho-dihydroxyphenylalkylamine that is derived from the common cellular metabolite tyrosine. For example, the catecholamines dopamine and norepinephrine are synthesized from tyrosine as follows: tyrosine is converted to dihydroxyphenylalamine (DOPA) by the enzyme tyrosine hydroxylase (TH), DOPA to dopamine by the enzyme aromatic L-amino acid decarboxylase (AADC), and dopamine to norepinephrine by the enzyme dopamine .beta.-hydroxylase (DBH). The rate limiting step for both dopamine and norepinephrine synthesis is the conversion of tyrosine into DOPA by TH. In addition, dopamine can be converted to dihydroxyphenylacetic acid (DOPAC) by the enzymes monoamine oxidase (MAO) and aldehyde dehydrogenase.
The exact mechanisms that regulate neuronal phenotype or even neuronal cell fate determination are not well understood. Developmental studies, however, have identified some genes that appear involved. Briefly, vertebrate nervous systems develop in stereotypic positions along the dorso-ventral (D-V) and anterior-posterior (A-P) axes of the neural tube (Tanabe et al., Science 274:1115-1123 (1996)). Transplantation and explant culture studies confirmed that signaling centers instruct cell fates along the A-P and D-V axes. A characteristic common to these centers is the interaction of receptor-ligand pairs to modify cell fate. Sonic hedgehog (Shh) and bone morphogenetic protein (BMP) are two such polypeptides that regulate cell fate along the D-V axis. Fibroblast growth factor-2 (FGF-2), FGF-8, retinoic acid (RA), and Wnt1 influence cell fate along the A-P axis. In each case, signaling induces downstream changes that are reflected in the patterning of transcription factor expression (Crossley et al., Nature 380:66-68 (1996); Lumsden and Krumlauf, Science 274:1109-1114 (1996); Shimamura et al., Development 124:2709-2718 (1997); and Vollmer et al, J. Neurochem. 71:1-19 (1998)).
Using explant cultures, intersections of Shh and FGF-8 signaling created induction sites for dopaminergic neurons in the midbrain and forebrain (Ye et al., Cell 93:755-766 (1998)). In addition, Nurr1, an orphan receptor belonging to the nuclear receptor superfamily (Law et al., Mol. Endocrinol. 6:2192-2135 (1992) and Zetterstrom et al., Mol. Endocrinol. 10:1656-1666 (1996)), and the bicoid-related homeobox factor Ptx3/Pitx3 (Semina et al., Human Mol. Genet. 6:2109-2116 (1997); Semina et al., Nature Genet. 19:167-170 (1998); and Smidt et al., Proc. Natl. Acad. Sci. USA 94:13305-13310 (1997)) appear to be involved in midbrain dopaminergic determination.
Briefly, Nurr1 is expressed at embryonic day (E) 10.5 in the ventral aspect of the mesencephalic flexure and continues to be expressed into adulthood (Zetterstrom et al., Mol. Endocrinol. 10:1656-1666(1996) and Zetterstrom et al., Mol. Brain Res. 41:111-120(1996)). Ptx3 is expressed in ventral midbrain starting at E11.5, soon after Nurr1 begins to be expressed (Smidt et al., Proc. Natl. Acad. Sci. USA 94:13305-13310 (1997) and Saucedo-Cawdenas et al., Proc. Natl. Acad. Sci. USA 95:4013-4018 (1998)). Nurr1-null mice lack midbrain dopaminergic neurons and die within 24 h after birth (Zetterstrom et al., Science 276:248-250 (1997); Saucedo-Cawdenas et al., Proc. Natl. Acad. Sci. USA 95:4013-4018 (1998); and Castillo et al., Mol. Cell. Neurosci. 11:36-46 (1998)). In addition, dopamine is absent in the substantia nigra and ventral tegmental area of Nurr1-null mice (Castillo et al., Mol. Cell. Neurosci. 11:36-46 (1998)). However, TH immunoreactivity and mRNA expression in hypothalamic, olfactory, and lower brain stem regions were unaffected, and DOPA treatments, whether given to the pregnant dams or to the newborns, failed to rescue the Nurr1-null mice (Castillo et al., Mol. Cell. Neurosci. 11:36-46 (1998)).